**3. Antibiotic resistance: origin and current status**

The first concern regarding antimicrobial resistance appeared with the observation of penicillin resistant *Staphylococcus* in 1940 [7]. Initial few observations suggested that bacteria could destroy the drug by enzymatic degradation. Shortly thereafter, penicillin resistance became a substantial clinical problem. The first case of methicillin-resistant *Staphylococcus aureus* (MRSA) was identified in the United Kingdom in 1962 and in the United States in 1968 [9, 10]. In reality, this is true for many other pathogenic bacteria, including the *Enterobacteriaceae*, which have become resistant not only to the original penicillin but also to semisynthetic penicillins, cephalosporins and newer carbapenems [11]. Details about the development of the resistance in different classes of antibiotics are shown in the timeline (**Figure 1**) [7]. Antimicrobial resistance often occurs through various mechanisms such as inhibition of cell wall synthesis, nucleic acid synthesis, ribosome function, protein synthesis, folate metabolism and cell membrane function. The target can be (i) modified, as in the case of acetylation of aminoglycosides, (ii) destroyed (as the β-lactam antibiotics by the Introductory Chapter: Stepping into the Post-Antibiotic Era—Challenges and Solutions http://dx.doi.org/10.5772/intechopen.84486 3

**Figure 1.** Timeline showing antibiotic development and antimicrobial resistance.

**2. Modern antibiotic era**

2 Antimicrobial Resistance - A Global Threat

newer antibiotics in future.

of resistance especially in developing countries.

**3. Antibiotic resistance: origin and current status**

Modern antibiotic era began in 1904–1910 with Paul Ehrlich and Alexander Fleming [4, 5]. Initially, it was limited to the discovery of chemicals like inorganic mercury salts and organoarsenic compounds to treat syphilis. It was Paul Ehrlich who introduced the systemic screening approach that is the cornerstone of modern drug research trials [4]. Paul Ehrlich and his team synthesised hundreds of organo-arsenic derivatives of a very toxic drug Atoxyl and tested them in rabbits infected with syphilis. This approach led to the discovery of Salvarsan and later to a sulfa drug (Prontosil). The serendipitous discovery of penicillin by Alexander Fleming in 1928 changed the history of infectious diseases [5]. It was Florey and Chain who led the pathway for purification of penicillin and later to its mass production [6]. Interestingly enough, Fleming was the one who sounded the warning bells regarding the development of resistance to the penicillin, if not used properly. So, in a nutshell, discovery of the first three antimicrobials, Salvarsan, Prontosil and penicillin paved the pathway for the discovery of

The golden era of discovery of newer antibiotics continued and lasted till 1970s when most of the major classes like tetracyclines, methicillin, gentamicin, etc. were discovered [7]. This was followed by apparent absence of newer drug discovery with occasional antibiotic making an appearance here and there. Simultaneously, we made each newly discovered antibiotic ineffective after its launch by extensive use and misuse for trivial illnesses. The prime example of this is the fluoroquinolone, ciprofloxacin [8]. It was one of the most active, broad-spectrum antibiotics which had minimum side effects and a very good bioavailability upon oral use and soon became a drug of choice for many infections. Its extensive usage for gastroenteritis and respiratory infections, which were mostly viral in origin, led to the development of high level

The first concern regarding antimicrobial resistance appeared with the observation of penicillin resistant *Staphylococcus* in 1940 [7]. Initial few observations suggested that bacteria could destroy the drug by enzymatic degradation. Shortly thereafter, penicillin resistance became a substantial clinical problem. The first case of methicillin-resistant *Staphylococcus aureus* (MRSA) was identified in the United Kingdom in 1962 and in the United States in 1968 [9, 10]. In reality, this is true for many other pathogenic bacteria, including the *Enterobacteriaceae*, which have become resistant not only to the original penicillin but also to semisynthetic penicillins, cephalosporins and newer carbapenems [11]. Details about the development of the resistance in different classes of antibiotics are shown in the timeline (**Figure 1**) [7]. Antimicrobial resistance often occurs through various mechanisms such as inhibition of cell wall synthesis, nucleic acid synthesis, ribosome function, protein synthesis, folate metabolism and cell membrane function. The target can be (i) modified, as in the case of acetylation of aminoglycosides, (ii) destroyed (as the β-lactam antibiotics by the action of β-lactamases) and (iii) pumped out from the cell as in efflux pump mechanisms of resistance [12].

Unfortunately, true burden of antimicrobial resistance (AMR) remains unknown. There are many hindrances in estimating the burden of AMR. Incongruent data is available from public and private sectors; data are often not collected properly and contain little information of patient follow up. These problems are intensified in low- and middle-socioeconomic countries due to problems of inadequate surveillance, poor laboratory infrastructure and limited access to the crucial antimicrobials. According to a study from Vietnam and Thailand, prevalence of stool carriage of extended-spectrum beta-lactamase (ESBL)-producing *Escherichia coli* was 51.0 and 69.3%, respectively [13]. There is also an increasing prevalence of MDR Grampositive bacteria. Another study in Thailand and Indonesia showed that prevalence of MRSA carriage is around 8% in admitted patients [14, 15]. Similar or worse situation exists in other Asian countries including China, Pakistan, Bangladesh and India. Antimicrobial resistance is a global issue. Resistance genes spread throughout the world as recent database lists the existence of more than 20,000 potential resistance genes (r genes) of nearly 400 different types, predicted from available sequences [16]. It is difficult to estimate the exact AMR burden due to the lack of comprehensive and uniform data. Gram-negative bacteria possessing the capabilities of producing extended-spectrum beta-lactamases (ESBL), AmpC beta-lactamases and carbapenemases have emerged as a therapeutic challenge for medical fraternity [17]. *Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa*, and *Enterobacter* species have been classified into a group known as "ESKAPE" due to their ability to escape the action of antimicrobials [18]. Multiple mechanisms of antimicrobial resistance have been acquired by carbapenem-resistant *Enterobacteriaceae* (CRE), *P. aeruginosa* and *A. Baumannii* resulting in enhanced morbidity and mortality [19–23]. In the 1990s, emergence of ESBLs among different microorganisms on global level led to widespread and increased use of carbapenems giving rise to emergence of pandemic CRE [24]. The Centers for Disease Control and Prevention has categorised CRE as *urgent* and ESBL-producing Gramnegative bacteria as *serious* antibiotic threats in the USA [10].

treatment are incorrect in almost 30–50% of cases [32, 33]. Extensive usage occurs in ICUs and high-dependency units, and there too approximately, 30–60% of the usage is unnecessary or incorrect [33]. Studies from pharmacies of Vietnam show that 90% of antimicrobials are sold without a proper prescription [34]. Upper respiratory tract infections (URTI) are good example, for which antimicrobial are commonly prescribed over the counter. This illustrates the overuse of antimicrobials for a condition that is often self-limiting and generally of viral aetiology. Suboptimal doses of any antibiotic further promote the genetic alterations as well as mutagenesis in the bacteria which lead to the development of multi-

Introductory Chapter: Stepping into the Post-Antibiotic Era—Challenges and Solutions

http://dx.doi.org/10.5772/intechopen.84486

5

Antibiotics are widely used as growth promoters and to prevent infections in the livestock sector. In the United States alone, an estimated 80% of the sold antibiotics are used in farm animals [7]. In 2010, India was one of the world's largest consumers of antibiotics in the veterinary sector [35]. The resistant bacteria reach the consumers through food animal products, mainly meat. These bacteria constitute large pools of AMR genes that can be transferred to humans and pathogenic bacteria by natural horizontal gene transfer mechanisms. These bacteria, although some may only be transient and do not colonise the intestinal tract, reside long enough to interact with the host microbiota and may possibly acquire or release genes. They can also act as opportunistic pathogens in susceptible hosts and probably play a key role in the evolution and dissemination of AMR. The use of antibiotics in food not only leads to the emergence and spread of resistant bacteria but also can be hazardous to many types of nontargeted environmental microorganisms. High concentrations of therapeutic antibiotics tend to be lethal to most bacterial strains leaving little opportunity for selection of subpopulations that have low or intermediate resistant traits. On the other hand, low levels of antibiotics in environment like soil, water and sewage become grounds for the selection of resistant microorganisms leading to the development

Investment in antibiotic development research is no longer considered as an economically wise decision for pharmaceutical companies [36]. According to a study conducted in London, it was calculated that the net present value (NPV) of new antibiotics is only about \$50 million, compared to approximately \$1 billion for a drug used to treat a neuromuscular disease [37]. Other reasons include low cost of antibiotics, regulatory barriers and tendency to save the new drug for serious infections. In spite of global warnings issued by many agencies, very few new drug discoveries fail to keep pace with worsening resistance scenario. As declared by the CDC in 2013, the human race is moving into a new era of infectious disease: the post-antibiotic period [38]. Here are few examples of the MDR organisms which are considered a substantial threat to the humankind. They have been divided as "urgent," "serious" or "concerning" by

drug resistance in them.

**5.3. Extensive use in livestock sector**

of resistant gene pool or resistome [7, 12].

**5.4. Availability of few new antibiotics**

CDC [24, 39] (**Figure 2**).
